Prolinamide derivatives as thrombin inhibitors, preparation method and application thereof

Abstract

Provided are a compound of formula (I), pharmaceutically acceptable salts thereof, preparation methods and applications thereof for inhibiting thrombin, and applications in the treatment and prevention of thrombin-mediated and thrombin-related diseases.

The invention claimed is: 
     
       1. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein:
 A represents —SO 2 R 1 , —COR 1 , —R 2 COR 1 , or —R 2 CO 2 R 1 ; 
 
         wherein:
 R 1  represents cycloalkyl, aryl, —R 3 -cycloalkyl, —R 3 -aryl, or —NR 4 R 5 ; 
 wherein cycloalkyl and aryl are substituted with 1 or 2 substituents selected from the group consisting of hydroxyl, carboxyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, acyl, sulfonyl, sulfhydryl, alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, ester group, trifluoromethyl, and CONH 2 ; 
 R 2  and R 3  represent unsubstituted C 1˜6  alkyl; 
 R 4  and R 5  represent independently H or unsubstituted C 1˜6  alkyl; 
 D represents 
 
       
       
         
           
           
               
               
           
         
         
           F represents —NH—(CH 2 ) m —R 6 ; 
           wherein: 
           m represents 1; 
           R 6  represents unsubstituted 
         
       
       
         
           
           
               
               
           
         
         
           G represents 
         
       
       
         
           
           
               
               
           
         
         
           wherein: 
           n represents 0; and 
           R 7  represents H. 
         
       
     
     
       2. The compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof according to  claim 1 , characterized in that the compound is:
 N,N-dimethylaminosulfonyl-D-leucyl-L-prolyl-[(4-amidinophenyl)methyl]amide hydrochloride.